Phenyl or heteroaryl and tetrahydronaphthyl substituted diene compound having retinoid like biological activity

ABSTRACT

Compounds of Formula 1 ##STR1## wherein m is 1-4; R 1  -R 4  independently are hydrogen, lower alkyl of 1 to 6 carbons, Cl, Br, or I; R 5  is hydrogen, lower alkyl of 1 to 6 carbons, Cl, Br, I, lower alkoxy or lower thioalkoxy of 1-6 carbons; R 6  is hydrogen, lower alkyl, Cl, Br, I, OR 11 , SR 11 , OCOR 11 , SCOR 11 , NH 2 , NHR 11 , N(R 11 ) 2 , NHCOR 11  OR NR 11  --COR 11  ; R 20  is independently hydrogen or lower alkyl; Y is an aromatic group such as phenyl or naphthyl, or a heteroaryl group selected from a group consisting of pyridyl, thienyl, furyl, pyridazinyl, pyrimidinyl, pyrazinyl, thiazolyl and oxazolyl; A is (CH 2 ) n  where n is 0-5, lower branched chain alkyl having 3-6 carbons, cycloalkyl having 3-6 carbons, alkenyl having 2-6 carbons and 1 or 2 double bonds, alkynyl having 2-6 carbons and 1 or 2 triple bonds; B is hydrogen, COOH or a pharmaceutically acceptable salt thereof, COOR 8 , CONR 9  R 10 , --CH 2  OH, CH 2  OR 11 , CH 2  OCOR 11 , CHO, CH(OR 12 ) 2 , CHOR 13  O , --COR 7 , CR 7  (OR 12 ) 2 , or CR 7  OR 13  O , where R 7  is an alkyl, cycloalkyl or alkenyl group containing 1 to 5 carbons, R 8  is an alkyl group of 1 to 10 carbons, or a cycloalkyl group of 5 to 10 carbons, or R 8  is phenyl or lower alkylphenyl, R 9  and R 10  independently are hydrogen, an alkyl group of 1 to 10 carbons, or a cycloalkyl group of 5-10 carbons, or phenyl or lower aklylphenyl, R 11  is lower alkyl, phenyl or lower alkylphenyl, R 12  is lower alkyl, and R 13  is divalent alkyl radical of 2-5 carbons, have retinoid like biological activity. In the compounds of the invention the A--B and the butadiene groups are attached to adjacent aromatic carbons of the Y moiety.

CROSS-REFERENCE TO RELATED APPLICATION

The present application is a divisional of application Ser. No.08/138,275 filed on Oct. 18, 1993 U.S. Pat. No. 5,475,022.

BACKGROUND OF THE INVENTION

1. Field of the Invention

The present invention is directed to novel compounds which have retinoidlike biological activity. More specifically, the present inventionrelates to diene compounds substituted with a phenyl or heteroaromaticmoiety where the ring connection is adjacent to a substituent group inthe heterocycle, the diene being further substituted with atetrahydronaphthyl or analogous group. The present invention alsorelates to pharmaceutical compositions comprising these compounds as theactive ingredient and to methods of using the compounds andcompositions.

2. Brief Description of the Background Art

The biological activity of retinoic acid is known and has been thesubject of numerous literature references.

A relatively large number of retinoic acid analogs (retinoid likecompounds) have been synthesized in the prior art, and are described innumerous patents and scientific publications. For example, U.S. Pat. No.4,326,055 discloses ethene derivatives which have a substituted phenylring and a substituted indane or tetrahydronaphthalene group. Thecompounds are described as tumor inhibiting agents, and useful fortreating dermatological conditions and rheumatic illnesses.

U.S. Pat. No. 4,723,028 discloses diphenylethene (stilbene) derivativeswhich have retinoic acid-like activity.

U.S. Pat. No. 4,740,519 discloses certain aromatic heterocyclederivatives which have retinoic acid-like activity.

Published European Patent Application 0130795 discloses ethenederivatives, where the ethene moiety is substituted by a substitutedphenyl group and by a substituted chroman, thiochroman or quinolinegroup. The compounds are useful for inhibiting the degradation ofcartilage in mammals.

European Patent Application 176034A (Published Apr. 2, 1986) disclosestetrahydronaphthalene compounds having an ethynylbenzoic group. U.S.Pat. No. 4,739,098 discloses compounds wherein three olefinic units fromthe acid-containing moiety of retinoic acid are replaced by anethynylphenyl functionality. These compounds have retinoic acid-likebiological activity.

Published German Patent Application DE 3529032 A1 discloses di-phenylsubstituted butadiene compounds having retinoid-like activity.

U.S. Pat. No. 4,810,804 (issued on Mar. 7, 1989) based on an applicationof the same inventor and assigned to the same assignee as the presentapplication, discloses such disubstituted acetylene compounds whereinone of the substituents of the acetylene group is a substituted phenylgroup, and the second substitutent is a substituted or unsubstituted6-chromanyl, 6-thiochromanyl or 6-tetrahydroquinolinyl group. Thecompounds disclosed and claimed in U.S. Pat. No. 4,810,864 have retinoicacid-like biological activity.

The publication Cancer Research 44, 190-195, January 1984 Dawson et. al.discusses the relationship between binding affinities to cellularretinoic acid binding protein and the biological potency of a new seriesof retinoids. The synthesis of the latter compounds is disclosed inDawson, Journal of Medicinal Chemistry, 1981, Vol. 24, No.5 591.

A publication titled "Aromatic Retinoic Acid Analogues Synthesis andPharmacological Activity" by M. I. Dawson et al. Journal of MedicinalChemistry 1981 Vo. 24 p 583-592 discusses structure activityrelationships of certain synthetic retinoids and describes the synthesisof certain phenyl and cyclohexenyl substituted butadienes andhexatrienes as retinoid analogs.

A publication by L. W. Spruce et al. titled Novel Heteroarotinoids:Synthesis and Biological Activity Journal of Medicinal Chemistry 1991Vol. 34, p. 430 describes certain thiochromanyl and cyclopropylsubstituted butadienes as retinoid analogs.

The synthesis of 2-furancarboxylic acid,5-(methylthio)-3-(4-phenyl-1,3-butadienyl)-,ethyl ester is disclosed inTetrahedron, 45(23), 7631-40 (Eng) 1989.

Several co-pending applications and recently issued patents of thepresent inventor, which are assigned to the assignee of the presentapplication, are directed to further compounds having retinoic acid-likeacitivity.

SUMMARY OF THE INVENTION

The present invention covers compounds of Formula 1 ##STR2## wherein mis 1-4;

R₁ -R₄ independently are hydrogen, lower alkyl of 1 to 6 carbons, F, Cl,Br, or I;

R₅ is hydrogen, lower alkyl of 1 to 6 carbons, F, Cl, Br, I, loweralkoxy or lower thioalkoxy of 1-6 carbons;

R₆ is hydrogen, lower alkyl, F, Cl, Br, I, OR₁₁, SR₁₁, OCOR₁₁, SCOR₁₁,NH2, NHR₁₁, N(R₁₁)₂, NHCOR₁₁ OR NR₁₁ --COR₁₁ ;

R₂₀ is independently hydrogen or lower alkyl;

Y is an aromatic group such as phenyl or naphthyl, or a heteroaryl groupselected from a group consisting of pyridyl, thienyl, furyl,pyridazinyl, pyrimidinyl, pyrazinyl, thiazolyl and oxazolyl;

A is (CH₂)_(n) where n is 0-5, lower branched chain alkyl having 3-6carbons, cycloalkyl having 3-6 carbons, alkenyl having 2-6 carbons and 1or 2 double bonds, alkynyl having 2-6 carbons and 1 or 2 triple bonds;

B is hydrogen, COOH or a pharmaceutically acceptable salt thereof,COOR₈, CONR₉ R₁₀, --CH₂ OH, CH₂ OR₁₁, CH₂ OCOR₁₁, CHO, CH(OR₁₂)₂, CHOR₁₃O , --COR₇, CR₇ (OR₁₂)₂, or CR₇ OR₁₃ O , where R₇ is an alkyl,cycloalkyl or alkenyl group containing 1 to 5 carbons, R₈ is an alkylgroup of 1 to 10 carbons, or a cycloalkyl group of 5 to 10 carbons, orR₈ is phenyl or lower alkylphenyl, R₉ and R₁₀ independently arehydrogen, an alkyl group of 1 to 10 carbons, or a cycloalkyl group of5-10 carbons, or phenyl or lower aklylphenyl, R₁₁ is lower alkyl, phenylor lower alkylphenyl, R₁₂ is lower alkyl, and R₁₃ is divalent alkylradical of 2-5 carbons.

In the compounds of the invention the diene and A--B groups are attachedto adjacent aromatic carbons such that for example in the compound whereY is phenyl, the phenyl moiety is ortho substituted.

In a second aspect, this invention relates to the use of the compoundsof Formula 1 as regulators for cell proliferation and differentiation,and particularly as agents for treating dermatoses, such as ache,Darier's disease, psoriasis, icthyosis, eczema, atopic dermatitis, andfor treating and preventing malignant hyperproliferative diseases suchas epithelial cancer, breast cancer, prostatic cancer, head and neckcancer and myeloid leukemias, for reversing and preventingartherosclerosis and restenosis resulting from neointiuralhyperproliferation, for treating and preventing other non-malignanthyperproliferative diseases such as endometrial hyperplasia, benignprostatic hypertrophy, proliferative vitreal retirropathy anddysplasias, for treating autoimmune diseases and immunological disorders(e.g. lupus erythematosus), for treating chronic inflammatory diseasessuch as pulmonary fibrosis, for treating and preventing diseasesassociated with lipid metabolism and transport such as dyslipidemias,for promoting wound healing, for treating dry eye syndrome and inreversing and preventing the effects of sun damge to skin.

The present invention also relates to a pharmaceutical formulationcomprising a compound of Formula 1 in admixture with a pharmaceuticallyacceptable excipient.

The compounds of this invention of Formula 1 can be made by a processwhich comprises: reacting a compound of Formula 2 with a base andsubsequently with a compound of Formula 3 ##STR3## where the symbols areas described above in connection with Formula 1, except that for thisreaction B is H, or a protected acid, alcohol, aldehyde or ketone. TheA--B group on the Y ring is separated only by one aromatic bond from theR₄ --CO moiety, giving the corresponding compound of Formula 1,

or homologating a compound of Formula 1 where A is (CH₂)_(n) and n is0-4 to give an acid of Formula 1; converting an acid of Formula 1 to asalt; or forming an acid addition salt; converting an acid of Formula 1to an ester; or converting an acid of Formula 1 to an amide; or reducingan acid of Formula 1 to an alcohol or aldehyde; or converting an alcoholof Formula 1 to an ether or ester; or oxidizing an alcohol of Formula 1to an aldehyde; or converting an aldehyde of Formula 1 to an acetal; orconverting a ketone of Formula 1 to a ketal.

GENERAL EMBODIMENTS Definitions

The term alkyl refers to and covers any and all groups which are knownas normal alkyl, branch-chain alkyl and cycloalkyl. The term alkenylrefers to and covers normal alkenyl, branch chain alkenyl andcycloalkenyl groups having one or more sites of unsaturation. Loweralkyl means the above-defined broad definition of alkyl groups having 1to 6 carbons, and as applicable, 3 to 6 carbons for branch chained andcyclo-alkyl groups. Lower alkenyl is defined similarly having 2 to 6carbons for normal alkenyl, and 3 to 6 carbons for branch chained andcycloalkenyl groups.

The term "ester" as used here refers to and covers any compound fallingwithin the definition of that term as classically used in organicchemistry. Where B (of Formula 1, is --COOH, this term covers theproducts derived from treatment of this function with alcohols,preferably with aliphatic alcohols having 1-6 carbons. Where the esteris derived from compounds where B is --CH₂ OH, this term coverscompounds of the formula --CH₂ OOCR₁₁ where R₁₁ is any substituted orunsubstituted aliphatic, aromatic or aliphatic-aromatic group,preferably with 1-6 carbons in the aliphatic portions.

Preferred esters are derived from the saturated aliphatic alcohols oracids of ten or fewer carbon atoms or the cyclic or saturated aliphaticcyclic alcohols and acids of 5 to 10 carbon atoms. Particularlypreferred aliphatic esters are those derived from lower alkyl acids oralcohols. Also preferred are the phenyl or lower alkylphenyl esters.

Amide has the meaning classically accorded that term in organicchemistry. In this instance it includes the unsubstituted amides and allaliphatic and aromatic mono-and di-substituted amides. Preferred amidesare the mono- and di-substituted amides derived from the saturatedaliphatic radicals of ten or fewer carbon atoms or the cyclic orsaturated aliphatic-cyclic radicals of 5 to 10 carbon atoms.Particularly preferred amides are those derived from lower alkyl amines.Also preferred are mono- and di-substituted amides derived from thephenyl or lower alkylphenyl amines. Unsubstituted amides are alsopreferred.

Acetals and ketals include the radicals of the formula --CK where K is(--OR)₂. Here, R is lower alkyl. Also, K may be --OR₁ O-- where R₁ islower alkyl of 2-5 carbon atoms, straight chain or branched.

A pharmaceutically acceptable salt may be prepared for any compound usedin the method of treatment of this invention, if the compound has afunctionality capable of forming such salt, for example an acid or anamine functionality. A pharmaceutically acceptable salt may be any saltwhich retains the activity of the parent compound and does not impartany deleterious or untoward effect on the subject to which it isadministered and in the context in which it is administered.

Such a salt may be derived from any organic or inorganic acid or base.The salt may be a mono or polyvalent ion. Of particular interest wherethe acid function is concerned are the inorganic ions, sodium,potassium, calcium, and magnesium. Organic amine salts may be made withamines, particularly ammonium salts such as mono-, di- and trialkylamines or ethanol amines. Salts may also be formed with caffeine,tromethamine and similar molecules. Where there is a nitrogensufficiently basic as to be capable of forming acid addition salts, suchmay be formed with any inorganic or organic acids or alkylating agentsuch as methyl iodide. Preferred salts are those formed with inorganicacids such as hydrochloric acid, sulfuric acid or phosphoric acid. Anyof a number of simple organic acids such as mono-, di- or tri-acid mayalso be used.

The compounds of the present invention which comprise novel compositionof matter, contain at least two double bonds and therefore may havetrans and cis (E and Z) isomers. In addition, some of the compounds usedin the method of treatment of the present invention may contain one ormore chiral centers and therefore exist in enantiomeric anddiastereomeric forms. The scope of the present invention is intended tocover all such isomers per se, as well as mixtures of cis and transisomers, mixtures of diastereomers and racemic mixtures of enantiomers(optical isomers) as well.

Methods of Administration

The compounds of this invention may be administered systemically ortopically, depending on such considerations as the condition to betreated, need for site-specific treatment, quantity of drug to beadministered, and similar considerations.

In the treatment of dermatoses particularly, topical administration maybe used, though in certain cases such as treatment of severe cysticacne, oral administration may be preferred. Any common topicalformulation such as a solution, suspension, gel, ointment, or salve andthe like may be used. Preparation of such topical formulations are welldescribed in the art of pharmaceutical formulations as exemplified, forexample, by Remington's Pharmaceutical Science, Edition 17, MackPublishing Company, Easton, Pa. For topical application, these compoundscould also be administered as a powder or spray, particularly in aerosolform.

If the drug is to be administered systemically, it may be confected as apowder, pill, tablet or the like, or as a syrup or elixir for oraladministration. For intravenous or intraperitoneal administration, thecompound will be prepared as a solution or suspension capable of beingadministered by injection. In certain cases, it may be useful toformulate these compounds in suppository form or as an extended releaseformulation for deposit under the skin or intermuscular injection.

Other medicaments can be added to such topical formulation for suchsecondary purposes as treating skin dryness, providing protectionagainst light; other medications for treating dermatoses, preventinginfection, reducing irritation, inflammation and the like.

Treatment of dermatoses or any other indications known or discovered tobe susceptible to treatment by retinoid like compounds will be effectedby administration of the therapeutically effective dose of one or morecompounds in accordance with the instant invention. A therapeuticconcentration will be that concentration which effects reduction of theparticular condition, or retards its expansion. In certain instances,the drug potentially could be used in a prophylactic manner to preventonset of a particular condition. A given therapeutic concentration willvary from condition to condition and in certain instances may vary withthe severity of the condition being treated and the patient'ssusceptibility to treatment. Accordingly, a given therapeuticconcentration will be best determined at the time and place throughroutine experimentation. However, it is anticipated that in thetreatment of, for example, acne, or other such dermatoses, that aformulation containing between 0.001 and 5 percent by weight, preferablyabout 0.01 to 1% will usually constitute a therapeutically effectiveconcentration. If administered systemically, an amount between 0.01 and100 mg per kg body weight per day, but preferably about 0.1 to 10 mg/kg,will effect a therapeutic result in most instances.

BIOLOGICAL ACTIVITY

The retinoid-like activity of these compounds is confirmed through theclassic measure of retinoic acid activity involving the effects ofretinoic acid on ornithine decarboxylase. The original work on thecorrelation between retinoic acid and decrease in cell proliferation wasdone by Verma & Boutwell, Cancer Research, 1977, 37,2196-2201. Thatreference discloses that ornithine decarboxylase (ODC) activityincreased precedent to polyamine biosynthesis. It has been establishedelsewhere that increases in polyamine synthesis can be correlated orassociated with cellular proliferation. Thus, if ODC activity could beinhibited, cell hyperproliferation could be modulated. Although allcauses for ODC activity increases are unknown, it is known that12-0-tetradecanoylphorbol-13-acetate (TPA) induces ODC activity.Retinoic acid inhibits this induction of ODC activity by TPA. An assayessentially following the procedure set out in Cancer Res: 1662-1670,1975 may be used to demonstrate inhibition of TPA induction of ODC bycompounds of this invention. The results of this assay for certainexamplary compounds of the invention are shown in Table 1 below.

                  TABLE 1                                                         ______________________________________                                                    % ODC Inhibition at 1.0 μM                                     Compound #  concentration                                                     ______________________________________                                        1           37                                                                2           36                                                                6           100*                                                              7           79                                                                8           75                                                                9           56                                                                11          26                                                                12          42                                                                13          60                                                                14          72                                                                17          79                                                                19          73                                                                24          88                                                                ______________________________________                                         *value determined by linear regression of data collected at 30, 100, 300      nanomolar concentrations.                                                

PREFERRED EMBODIMENTS

Referring now to the FORMULA 1 and with reference to the symbol m, thepreferred compounds of the invention are 5,6,7,8-tetrahydronaphthalenederivatives wherein m is 2.

With reference to the symbol Y, the preferred compounds of the inventionare those where Y is phenyl, furyl, or thienyl.

The substituent R₁ is preferably hydrogen or lower alkyl, morepreferably lower alkyl, and most preferably methyl. The substituents R₂,R₃ and R₄ preferably are hydrogen or lower alkyl, more preferably H. Thesubstitutent R₅ is preferably hydrogen or lower alkyl, more preferablyhydrogen. The substituent R₆ is preferably hydrogen, lower alkyl, orhalogen, more preferably H or methyl.

The substituents R₂₀ preferably are lower alkyl, more preferably methyl.

With regard to the side chain (substituent) on the phenyl or heteroarylgroup Y, compounds are preferred where A is (CH₂)_(n) and n is 0; and Bis --COOH, and alkali metal salt or organic amine salt, or a lower alkylester thereof, or --CH₂ OH and the lower alkyl ester and ether thereof,(formed with a lower alkanol) or --CHO and acetal derivatives thereof.

The most preferred compounds of the present invention are shown in Table2, with reference to Formula 4. In Formula 4 and elsewhere in thisspecification wavy lines connected to an ethylene moiety (double bondedcarbons) indicate that the configuration about that double bond may becis (Z) or trans (E). With particular reference to FIG. 4 (and elsewherewhere it is applicable in the present description) the butadiene moietyis numbered such that the double bonded carbons more proximate to thetetrahydronaphthalene ring are carbons 4 and 3. Consequently, from "leftto right" in the structural formula of FIG. 4 (and elsewhere whereapplicable) trans configuration of the first double bond is designatedin the chemical name and in Table 2 as "3E", and trans configuration ofthe second double bond (left to right) is designated in the chemicalname and in Table 2 as "1E". In Table 2 the Y substituent is describedfirst by reference to the point of attachment of the respective aryl orheteroaryl moiety to carbon-1 of the butadiene moiety, and then thesecond position of substitution (in case of Formula 4 with the COOR₈group) is designated. For example for Compound 1 the designation "2furyl (3 substituted)" means that the 2 position of the furan ring isattached to the butadiene moiety and that the furan ring is substitutedwith an R₈ (CH₃) group in its 3 position. The compound number is anumber assigned to certain compounds for ease of reference in thepresent description. ##STR4##

                  TABLE 2                                                         ______________________________________                                                Stereo-  Stereo-                                                      Compound                                                                              chemistry                                                                              chemistry                                                    No.     at 3     at 1     R.sub.6                                                                             Y       R.sub.8                               ______________________________________                                        1       3E       1E       CH.sub.3                                                                            2-furyl (3-                                                                           CH.sub.3                                                              substituted)                                  2       3Z       1E       CH.sub.3                                                                            2-furyl (3-                                                                           CH.sub.3                                                              substituted)                                  3       3E       1E       CH.sub.3                                                                            1-phenyl (2-                                                                          CH.sub.2 CH.sub.3                                                     substituted)                                  4       3Z       1E       CH.sub.3                                                                            1-phenyl (2-                                                                          CH.sub.2 CH.sub.3                                                     substituted)                                  5       3Z       1E       H     1-phenyl (2-                                                                          CH.sub.3                                                              substituted)                                  6       3E       1E       H     1-phenyl (2-                                                                          CH.sub.3                                                              substituted)                                  7       3E       1E       CH.sub.3                                                                            1-phenyl (2-                                                                          H                                                                     substituted)                                  8       3Z       1E       CH.sub.3                                                                            1-phenyl (2-                                                                          H                                                                     substituted)                                  9       3Z       1E       CH.sub.3                                                                            2-furyl (3-                                                                           H                                                                     substituted)                                  10      3E       1E       CH.sub.3                                                                            2-furyl (3-                                                                           H                                                                     substituted)                                  11      3E       1E       H     2-furyl (3-                                                                           CH.sub.3                                                              substituted)                                  12      3Z       1E       H     2-furyl (3-                                                                           CH.sub.3                                                              substituted)                                  13      3E       1E       H     2-furyl (3-                                                                           H                                                                     substituted)                                  14      3Z       1E       H     2-furyl (3-                                                                           H                                                                     substituted)                                  15      3E       1E       CH.sub.3                                                                            3-thienyl (2-                                                                         CH.sub.2 CH.sub.3                                                     substituted)                                  16      3Z       1E       CH.sub.3                                                                            3-thienyl (2-                                                                         CH.sub.2 CH.sub.3                                                     substituted)                                  17      3E       1E       CH.sub.3                                                                            3-thienyl (2-                                                                         H                                                                     substituted)                                  18      3Z       1E       CH.sub.3                                                                            3-thienyl (2-                                                                         H                                                                     substituted)                                  19      3E       1Z       CH.sub.3                                                                            3-furyl (2-                                                                           CH.sub.2 CH.sub.3                                                     substituted)                                  20      3E       1Z       CH.sub.3                                                                            2-thienyl (3-                                                                         CH.sub.3                                                              substituted)                                  21      3E       1E       CH.sub.3                                                                            2-thienyl (3-                                                                         CH.sub.3                                                              substituted)                                  22      3E       1E       CH.sub.3                                                                            2-thienyl (3-                                                                         H                                                                     substituted)                                  23      3E       1Z       CH.sub.3                                                                            2-thienyl (3-                                                                         H                                                                     substituted)                                  24      3E       1E       CH.sub.3                                                                            1-phenyl (2                                                                           H                                                                     substituted)                                  ______________________________________                                    

Synthetic Processes for Preparing Compounds of the Invention

It is anticipated that the compounds of this invention can be made by anumber of different synthetic chemical pathways. To illustrate thisinvention, there is here laid out a series of steps which will providethe compounds of Formula 1 where m is 2, (tetrahydronaphthalenederivatives) when such synthesis is followed in tone and in spirit. Thesynthetic chemist will readily appreciate that the conditions set outhere are specific embodiments which can be generalized to any and all ofthe compounds represented by Formula 1. Specifically, in order toprepare the compounds of the invention where m is 1, 3, or 4 thesequence of reactions outlined in Reaction Scheme 1 is followed, but thesequence is started with a compound which is the indane,cycloheptanobenzene or cyclooctanobenze analog of Formula 5. ##STR5##

Reaction Scheme 1 shows a synthetic route to the compounds of theinvention. A 5,5,7,8-tetrahydronapthalene compound of Formula 5, whichhas the desired R₅, R₆, and R₂₀ substitutents (as defined in connectionwith Formula 1) is reacted under Friedel Crafts like conditions with areagent such as R₁ COCl (R₁ is defined in connection with Formula 1) tointroduce the R₁ --CO ketone function into the 2-position of thetetrahydronaphthalene nucleus. When R₁ is methyl then the reagent in theFriedel Crafts type reaction is typically acetyl chloride. The ketone ofFormula 6 is reacted with vinyl magnesium bromide to give the tertiaryalcohol of Formula 7. The alcohol of Formula 7 is reacted withtriphenylphosphine hydrobromide. This reaction results in migration ofthe double bond and formation of the triphenylphosphonium salt ofFormula 8 where the triphenylphosphonium moiety is attached to a primarycarbon. The double bond obtained in this process is usuallypredominantly of trans (E) configuration. The triphenylphosphonium saltof Formula 8 is a Wittig reagent, which is reacted with the aromatic orheteroaromatic aldehyde or ketone of Formula 9 to provide the dienecompound of Formula 10. In Formula 9 the symbols Y, R₄ and R₈ aredefined as in connection with Formula 1, and also with the conditionthat the carbonyl (R₄ CO--) and and carboxylic acid ester (COOR₈)substituents are attached to adjacent aromatic or heteroaromatic carbons(ortho substitution). The Wittig reaction is typically conducted in thepresence of a base, such as 1,2-epoxybutane. The double bond formed inthe Wittig reaction is a mixture of cis (Z) and trans (E) isomers, butthe ratio of the trans (E) isomer can be increased by isomerization withiodine. The cis and trans isomers can usually be separated byappropriate techniques such as high pressure liquid chromatography(HPLC).

The Wittig reaction between the triphenylphosphonium salt of Formula 8and the aldehyde or ketone of Formula 9 can also be conducted in thepresence of n-BuLi or other appropriate bases.

The compound of Formula 10 which is formed as a result of the Wittigreaction has the essential structural features of the compounds used inaccordance with the present invention. Thus, the compound of Formula 10may be the target compound made in accordance with the invention, (inthis case Formula 10 depicts compounds of Formula 1) or may be readilyconverted into the target compound by such steps as salt formation,esterification, deesterification, homologation, amide formation and thelike. These steps are further discussed below.

Specifically, the compounds of Formula 10 may be subjected to furthertransformations, particularly as far as synthetic transformation of theCOOR₈ group is concerned. As far as the synthesis of compounds analogousto the compounds of Formula 10, but differring therefrom in thefunctionality of the A--B group (see for example Formula 1) isconcerned, (and by extension of the principles to any and all compoundsof the invention) the following further well known and published generalprinciples and synthetic methodology are noted.

Carboxylic acids are typically esterified by refluxing the acid in asolution of the appropriate alcohol in the presence of an acid catalystsuch as hydrogen chloride or thionyl chloride. Alternatively, thecarboxylic acid can be condensed with the appropriate alcohol in thepresence of dicyclohexylcarbodiimide and dimethylaminopyridine. Theester is recovered and purified by conventional means. Acetals andketals are readily made by the method described in March, "AdvancedOrganic Chemistry," 2nd Edition, McGraw-Hill Book Company, p 810).Alcohols, aldehydes and ketones all may be protected by formingrespectively, ethers and esters, acetals or ketals by known methods suchas those described in McOmie, Plenum Publishing Press, 1973 andProtecting Groups, Ed. Greene, John Wiley & Sons, 1981.

A means for making compounds where A is (CH₂)_(n) (n is 1-5) is tosubject the compounds of Formula 1, (or of Formula 10) where B is anacid or other function, to homologation, using the well knownArndt-Eistert method of homologation, or other known homologationprocedures.

Compounds of Formula 1, where A is an alkenyl group having one or moredouble bonds can be made for example, by having the requisite number ofdouble bonds incorporated into the aryl or heteroaryl intermediate whichis coupled as an aldehyde or ketone with the triphenylphosphonium saltof Formula 8. Generally speaking, such compounds where A is anunsaturated carbon chain can be obtained by synthetic schemes well knownto the practicing organic chemist; for example by Wittig and likereactions, or by introduction of a double bond by elimination of halogenfrom an alpha-halo-carboxylic acid, ester or like carboxaldehyde.Compounds of Formula 1 where the A group has a triple (acetylenic) bondcan be made by using the corresponding aryl or heteroaryl aldehyde orketone intermediate. Such intermediate can be obtained by reactions wellknown in the art, for example, by reaction of a corresponding methylketone with strong base, such as lithium diisopropyl amide.

The acids and salts derived from compounds of Formula 1 and of Formula10 are readily obtainable from the corresponding esters. Basicsaponification with an alkali metal base will provide the acid. Forexample, an ester of Formula 1 or of Formula 10 may be dissolved in apolar solvent such as an alkanol, preferably under an inert atmosphereat room temperature, with about a three molar excess of base, forexample, potassium hydroxide. The solution is stirred for an extendedperiod of time, between 15 and 20 hours, cooled, acidified and thehydrolysate recovered by conventional means.

The amide may be formed by any appropriate amidation means known in theart from the corresponding esters or carboxylic acids. One way toprepare such compounds is to convert an acid to an acid chloride andthen treat that compound with ammonium hydroxide or an appropriateamine. For example, the acid is treated with an alcoholic base solutionsuch as ethanolic KOH (in approximately a 10% molar excess) at roomtemperature for about 30 minutes. The solvent is removed and the residuetaken up in an organic solvent such as diethyl ether, treated with adialkyl formamide and then a 10-fold excess of oxalyl chloride. This isall effected at a moderately reduced temperature between about -10degrees and +10 degrees C. The last mentioned solution is then stirredat the reduced temperature for 1-4 hours, preferably 2 hours. Solventremoval provides a residue which is taken up in an inert organic solventsuch as benzene, cooled to about 0 degrees C. and treated withconcentrated ammonium hydroxide. The resulting mixture is stirred at areduced temperature for 1-4 hours. The product is recovered byconventional means.

Alcohols are made by converting the corresponding acids to the acidchloride with thionyl chloride or other means (J. March, "AdvancedOrganic Chemistry", 2nd Edition, McGraw-Hill Book Company), thenreducing the acid chloride with sodium borohydride (March, Ibid, pg.1124), which gives the corresponding alcohols. Alternatively, esters maybe reduced with lithium aluminum hydride at reduced temperatures.Alkylating these alcohols with appropriate alky halides under Williamsonreaction conditions (March, Ibid, pg. 357) gives the correspondingethers. These alcohols can be converted to esters by reacting them withappropriate acids in the presence of acid catalysts ordicyclohexylcarbodiimide and dimethlaminopyridine.

Aldehydes can be prepared from the corresponding primary alcohols usingmild oxidizing agents such as pyridinium dichromate in methylenechloride (Corey, E. J., Schmidt, G., Tet. Lett., 399, 1979), or dimethylsulfoxide/oxalyl chloride in methylene chloride (Omura, K., Swern, D.,Tetrahedron, 1978, 34, 1651).

Ketones can be prepared from an appropriate aldehyde by treating thealdehyde with an alkyl Grignard reagent or similar reagent followed byoxidation.

Acetals or ketals can be prepared from the corresponding aldehyde orketone by the method described in March, Ibid, p 810.

With regard to the aryl or heteroaryl intermediate compounds of Formula9, these are either available by procedures described in the chemicalliterature and therefore readily accessible to the practicing organicchemist, or can be readily prepared by adaptation of such literatureprocedures. Actual experimental processes for synthesizing severalintermediates corresponding to Formula 9, such as2-carboetoxy-3-furaldehyde, 3-carbomethoxy-2-thiophenecarboxaldehyde,2-carbomethoxybenzaldehyde, 2-carboethoxy-3-thiophenecarboxaldehyde, aredescribed below.

SPECIFIC EXAMPLES 1- 8,8-dimethyl (5,6,7,8-tetrahydronaphthalen)-2-yl!ethanol and 1- 8,8-dimethyl (5,6,7,8-tetrahydronaphthalen)-3-yl! ethanol

To a stirred solution of 4.27 g (32.0 mmol) of anhydrous aluminumchloride in 15 ml of methylene chloride at 0° C. was added a solution of4.0 g (25.0 mmol) of 1,1-dimethyltetralin (Davidson et al. J. Amer.Chem. Soc. 1934, 56 p 962) and 2.35 g (30.0 mmol) of acetyl chloride in5 ml of methylene chloride. The mixture was allowed to warm to roomtemperature over a period of one hour and then treated with 70 ml of icewater. The organic layer was isolated and washed with 20 ml of diluteHCl, 40 ml of water, and 40 ml of brine and dried (MgSO4). Solvent wasremoved in-vacuo and the residue was purified using fractionaldistillation (97°-99° C., 0.1 mm). The resulting methyl 8,8-dimethyl(5,6,7,8-tetrahydronaphthalen)-2-yl! ketone and methyl 8,8-dimethyl(5,6,7,8-tetrahydronaphthalen)-3-yl! ketone isomers were separable onlyafter reduction to the corresponding alcohols. To this end, lithiumaluminum hydride (0.250 g, 6.7 mmol) in 30 ml of dry ether was addeddropwise to a solution of 4.0 g (19.8 mmol) of methyl 8,8-dimethyl(5,6,7,8-tetrahydronaphthalen)-2-yl! ketone and methyl 8,8-dimethyl(5,6,7,8-tetrahydronaphthalen)-3-yl! ketone in 10 ml of anhydrous ether.The mixture was refluxed gently for 30 minutes and treated with ethylacetate, water, and dilute hydrochloric acid. The organic layer waswashed with water, brine and dried (MgSO4). Solvent was removed in-vacuoand the resulting isomeric mixture was purified and separated, usingHPLC (Whatman M20 partisil, 10% ethyl acetate in hexanes at 9.9 ml perminute) to give the title compounds as colorless oils: 1- 8,8-dimethyl(5,6,7,8-tetrahydronaphthalen)-2-yl! ethanol, PMR(CDCl₃): δ 1.28 (6H,s), 1.47 (3H, d, J˜6.7 Hz), 1.65 (2H, m), 1.78 (2H, m), 2.74 (2H, t,J˜6.3 Hz), 4.82(1H, q, J˜6.7 Hz), 7.02 (1H,d,J˜7.8 Hz), 7.08 (1H, dd,J˜1.8 Hz, J˜7.8 Hz), 7.32 (1H, d, J˜1.8 Hz), and 1 8,8-dimethyl(5,6,7,8-tetrahydronaphthalen)-3-yl! ethanol

PMR (CDCl₃): δ 1.27(6H,s),147(3H,d,J˜6.7 Hz), 1.65(2H,m), 1.78(2H,m),2.74(2H,t,J˜6.3 Hz), 4.78(1H,q,J˜6.7 Hz),7.02(1H,d,J˜1.8 Hz),7.11(1H,dd,J˜8.1 Hz, J˜1.8 Hz), 7.2(1H,d,J˜8.1 Hz)

Methyl 8,8 dimethyl (5,6,7,8-tetrahydronaphthalen)-2-yl! ketone

To a stirred solution of 2.44 g (11.96 mmol) of 1- 8,8-dimethyl(5,6,7,8-tetrahydrodnapthalen)-2-yl! ethanol in 35 ml of methylenechloride was added 6.75 g (17.9 mmol) of pyridinium dichromate and 0.33g (1.68 mmol) of pyridinium trifluroacetate at room temperature. Themixture was stirred for 16 hours and diluted with an equal volume ofpetroleum ether which caused a precipitate. The suspension was filteredthrough anhydrous MgSO₄ and silica gel (6 mm). Solvent was removedin-vacuo to give the title compound as a colorless liquid.

PMR(CDCl₃): δ 1.3 (6H,s), 1.67 (2H,m), 1.8 (2H,m), 2.55 (3H,s), 2.78(2H,m), 7.08 (1H, d, J˜8.0 Hz), 7.60 (1H, dd, J˜8.0 Hz, J˜1.8 Hz), 7.93(1H, d, J˜1.8 Hz).

Methyl 3,5,5,8,8-pentamethyl (5,6,7,8-tetrahydronaphthalen)-2-yl! ketone(Compound 30)

To a suspension of 6.71 g (50.3 mmol) of aluminum chloride in methylenechloride at 0° C. under argon was added a solution of 3.95 g (3.58 mL,50.3 mmol) of acetyl chloride and 10.21 g (41.9 mmol) of3,5,5,8,8-pentamethyl-5,6,7,8-tetrahydronaphthalene in methylenechloride. The resulting mixture was allowed to warm to room temperatureover a period of 3 hours with stirring. The mixture was recooled to 0°C. and 1N HCl was dropwise added. The mixture was then taken-up in waterand extracted three times with methylene chloride. The organic layerswere washed with 1N HCl, water, brine, and dried (MgSO₄). Solvent wasremoved in-vacuo and the resulting residue purified using flashchromatography to give the title compound as an ivory solid.

PMR (CDCl₃): δ 1.28 (6H, s), 1.30 (6H, s), 1.69 (4H, s), 2.49 (3H, s),2.57 (3H, s), 7.15 (1H, s), 7.67 (1H, s).

2-3,5,5,8,8-pentamethyl-5,6,7,8-tetrahydronapthalen)-2-yl!-but-3-en-2-ol(Compound 31)

To a stirred solution of 5.36 g (21.9 mmol) of methyl3,5,5,8,8-pentamethyl (5,6,7,8-tetrahydronapthalen)-2-yl! ketone(Compound 30) dissolved in 38 ml of freshly distilled tetrahydrofuran at0° C. under argon was added 37.4 ml of 1.0M solution of vinyl magnesiumbromide in tetrahydrofuran dropwise via syringe. The resulting mixturewas allowed to warm to room temperature over a period of 2 hours withstirring. The mixture was recooled to 0° C. and saturated aqueousammonium chloride solution was added dropwise. The mixture was thenextracted with ether and the ether layers were washed with water,saturated sodium bicarbonate, brine, and dried (MgSO4). The solvent wasremoved in-vacuo and the residue purified using flash chromatography(SiO₂, 3% ethyl acetate in hexanes) to give the title compound as awhite solid.

PMR (CDCl₃): δ 1.26(6H,s), 1.27 (6H,s), 1.66 (4H,s), 1.70(3H, s), 2.40(3H,s), 5.14 (1H, dd, J˜11 Hz, J˜1.2 Hz), 5.23 (1H, dd, J˜17 Hz, J˜1.2Hz), 6.16 (1H, dd, J˜11 Hz, J˜17 Hz), 7.04 (1H,s), 7.40 (1H,s).

Triphenyl3-(5,6,7,8-tetrahydro-3,5,5,8,8-pentamethyl-2-naphthalenyl)-2-buten-yl!phosphonium bromide (E) (Compound 32)

To a solution of 6.30 g (18.4 mmol) triphenylphosphonium hydrobromide in50 ml of methanol was added 5.02 g (18.4 mmol) of 2-3,5,5,8,8-pentamethyl-5,6,7,8-tetrahydronapthalen)-2-yl!-but-3-en-2-ol(Compound 31) in 50 ml of methanol via addition funnel dropwise at roomtemperature under argon. The solvent was removed in-vacuo after 16 hoursof stirring and the residue was purified using flash chormatography(SiO₂, 5% methanol in methylene chloride) to give the title compound asa white foam.

PMR(CDCl₃): δ 1.21(6H,s),1.23(6H,s),1.63(4H,s), 1.80(3H,d,J˜6 Hz),2.06(3H,m), 4.84(2H,m), 5.31(1H,s), 6.78(1H,s), 7.0(1H,s),7.65-7.97(15H,m).

2,5-Dichloro-2,5-dimethylhexane

Hydrogen chloride gas was bubbled through a suspension of 48 g (0.33mol) of 2,5-dimethyl-2,5-hexanediol in 600 ml conc. hydrogen chlorideuntil the solution was saturated. The resulting crystalline produce wascollected by filtration, washed repeatedly with water and dried on avacuum line to give the title compound as a crystalline white solid.

PMR (CDCl₃): δ 1.60 (12H, s), 1.94 (4H, s).

5,5,8,8-Tetramethyl-5,6,7,8-tetrahydronaphthalene

A vigorously stirred solution of 100 g (0.55 mol) of2,5-dichloro-2,5-dimethylhexane in 300 ml benzene was cooled in an icebath and treated with 45 g (0.34 mol) of anhydrous aluminum chloride insmall portions. This mixture was stirred at room temperature for 3hours, refluxed for 1 hour, cooled and poured into a mixture of ice andhydrogen chloride. The organic layer was recovered and the aqueous layerextracted with ether. Organic extracts were combined, washed with water,saturated Na₂ CO₃ and saturated NaCl solutions and dried (MgSO₄).

After removing the solvent, the residue was fractionally distilled (78°C., 0.8 mm) to give the title compound as a colorless liquid.

PMR (CDCl₃): δ 1.3 (12H, s), 1.7 (4H, s), 7.1 (2H, m), 7.5 (2H, m).

Methyl 5,5,8,8-tetramethyl(5,6,7,8-tetrahydronaphthalen)-2-yl! ketone(Compound 33)

A suspension of 3.45 g (25.9 mmol) aluminum chloride in 15 ml methylenechloride was cooled under argon in an ice/salt bath and treated whilestirring with a mixture of 4 g(21.2 mmol)5,5,8,8-tetramethyl-5,6,7,8-tetrahydro naphthalene and 1.94 g (24.7mmol) acetyl chloride via a dropping funnel over a period of 0.5 hours.Then the cooling bath was removed, the mixture stirred for 2 hours atroom temperature and the reaction quenched with ice. The organic layerwas recovered and the aqueous layer extracted with 2×50 ml methylenechloride.

The organic extracts were combined and washed with water, saturatedNaHCO₃ solution and dried (MgSO₄). Solvent was removed in vacuo and theresidue kugelrohr distilled (90° C.; 0.45 mm) to give the title compoundas a colorless oil.

PMR (CDCl₃): δ 1.32 (6H, s), 1.33 (6H, s), 1.72 (4H, s), 2.60 (3H, s),7.41 (1H, d, J˜8.8 Hz), 7.71 (1H, dd, J˜8.8, 2.6 Hz), 7.96 (1H, d, J˜2.6Hz).

2- 5,5,8,8-tetramethyl-(5,6,7,8-tetrahydronaphthalen)-2-yl!-2-but-3-enol(Compound 34)

To a stirred solution of 5.0 g (21.6 mmol) of freshly distilled(5,5,8,8-tetramethyl-(5,6,7,8-tetrahydronaphthalen)-2-yl! ketone(Compound 33) in 30 ml of tetrahydrofuran was added dropwise 43 ml (43.2mmol) of vinyl magnesium bromide at 0° C. under argon. The solution wasallowed to come to room temperature over a period of 72 hours withstirring. The mixture was quenched with saturated aqueous ammoniumchoride and extracted with ether. The ether layers were washed withwater, brine, and dried (MgSO₄). The solvent was removed in-vacuo andthe residue purified using flash chromatography (Silica gel, 5% ethylacetate in hexanes) to give the title compound as a yellow oil.

PMR (CDCl₃): δ 1.28 (6H,s), 1.30 (6H,s), 1.64 (3H,s), 1.68 (3H,s), 1.84(1H,s), 5.32 (1H,d, J˜17 Hz), 5.13 (1H,d, J˜10 Hz), 6.18 (1H, dd, J˜17Hz, J˜10 Hz), 7.2 (1H, dd J˜2 Hz, J˜8 Hz), 7.28 (1H,d,J˜8 Hz), 7.4 (1H,d, J˜2 Hz).

Triphenyl3-(5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthalenyl)-2-butenyl-phosphoniumbromide, (E) (Compound 35)

To a solution of 3.23 g (9.44 mmol) of triphenylphosphine hydrobromidein 30 ml of methanol was added 2.45 g (9.44 mmol) of 2-5,5,8,8-tetramethyl-(5,6,7,8-tetrahydtronapthalen)-2-yl!-2-but-3-enol.,(Compound 34) in 30 ml of methanol, dropwise at room temperature. Thesolvent was removed in-vacuo after 16 hours of stirring and the residuepurified using flash chromatography (SiO₂, 5% methanol in methylenechloride) to give the title compound as an off-white solid.

PMR (CDCl₃): δ 1.23(6H,s), 1.25(6H,s), 1.64(3H,s), 1.65(4H,s),4.88(2H,dd,J˜15 Hz, J˜8.0 Hz), 5.54-5.62(1H,m), 6.93(1H,dd,J˜8 Hz, J˜2Hz), 7.07(1H,d,J˜2 Hz), 7.20(1H,d,J˜8 Hz), 7.66-7.95(15H,m)

2-Carboethoxy-3-furaldehyde (Compound 40)

To a suspension of 7.02 g (68.7 mmol) of N,N'-trimethylethylene diaminein 100 ml of anhydrous tetrahydrofuran (chilled to -78° C.) was added44.6 ml (71.4 mmol) of 1.6M n-BuLi in hexanes. A dark yellow solutionwas formed. The solution was stirred at -78° C. under a blanket of argonfor 15 minutes. To the solution was added 6.24 g (64.9 mmol) ofdistilled 3-furaldehyde and the solution was stirred at -78° C. for 20minutes. To this solution was added 55.0 ml (71.4 mmol) of 1.3M solutionof BuLi in hexanes and the solution was stirred at -78° C. for 3 hours.The anion formed was transfered via cannula onto a solution of 7.75 g(6.8 ml, 71.4 mmol) of ethyl chloroformate in 20 ml of anhydroustetrahydrofuran (chilled to -78° C.). The resulting solution was allowedto warm to room temperature and stirred overnight (16.33 h). Thesolution was poured onto 1:10 10% HCl: ice (v/v) and the layers wereseparated. The aqueous layer was extracted with ether and the organicphases combined, dried over MgSO₄, filtered and concentrated in vacuo toyield a brown oil. Purification by flash chromatography (silica gel, 5%ethyl acetate in hexane) yielded the title compound as a white solid.

PMR (CDCl₃): d 1.45 (3H, t, J=7.1 Hz), 4.47 (2H, q, J=7.1 Hz), 6.92 (1H,d, J=1.8 Hz), 7.56 (1H, d, 1.8 Hz), 10.55 (1H, s).

2-Methyl-3-thiophenecarboxylic acid

To a suspension of 5.32 g (41.5 mmol) of 3-thiophenecarboxylic acid in100 ml of anhydrous tetrahydrofuran (chilled to -78° C.) was added 57.1ml (91.4 mmol) of 1.6M n-BuLi in hexanes. The cloudy suspension wasstirred at -78° C. under a blanket of argon for 40 minutes, and was thentransfered via canulla onto a solution of 59.05 g (25.9 ml, 416 mmol) ofmethyl iodide dissolved in 20 ml of anhydrous tetrahydrofuran (chilledto -78° C.). The resulting clear, colorless solution was allowed to warmto room temperature and stirred for 20 hours. A white solid was formed.The reaction mixture was concentrated in vacuo, partitioned between 75ml of sat. NH₄ Cl solution and 150 ml of ethyl ether, and the layersseparated. The aqueous phase was washed with 100 ml of ethyl ether andlayered with 100 ml of ethyl ether and acidified with 1N sulfuric acidsolution until all of the yellow emulsion dissapated. All organic phaseswere combined, washed with brine solution, dried over MgSO₄, filteredand concentrated in vacuo to yield an off-white solid. Purification byflash chromatography (silica gel, 75% ethyl acetate in hexane) yieldedthe title compound as an off white solid.

PMR (CDCl₃): d 2.78 (3H, s), 7.01 (1H, d, J=5.4 Hz), 7.45 (1H, d, 5.4Hz).

Methyl (2-methyl)3-thiophenecarboxylate

To a solution of 3.30 g (23.2 mmol) of 2-methyl-3-thiophenecarboxylicacid in 100 ml of acetone was added 16.04 g (116.1 mmol) of anhydrouspotassium carbonate and 16.47 g (7.2 ml, 116.1 mmol) of methyl iodide.The reaction mixture was allowed to stir at room temperature for 20.25hours. A white precipitate formed. The white precipitate was filtered,washed with ethyl ether and discarded. The filtrate was concentrated invacuo, partitioned between 250 ml of water and 250 ml of pentane and thelayers separated. The organic phase was washed with a saturated solutionof Na₂ SO₃, dried over Na₂ SO₄, filtered and concentrated by rotaryevaporation to give the title compound as a yellow oil which was usedwithout further purification.

PMR (CDCl₃): d 2.74 (3H, s), 3.85 (3H, s), 6.98 (1H, d, J=5.4 Hz), 7.38(1H, d, 5.4 Hz).

Methyl 3- 2-(imino-(N-oxide)-4-N,N-dimethylaniline)!thiophenecarboxylate

To a suspension of 3.79 g (24.3 mmol) of methyl(2-methyl)3-thiophenecarboxylate in 55 ml of CCl₄ was added 5.18 g (29.1mmol) of N-bromosuccinimide and 0.06 g (0.24 mmol) of benzoyl peroxide.A heterogeneous yellow mixture was formed. The mixture was refluxed for3 hours and turned dark orange in color. The mixture was allowed to stirat room temperature overnight. To the mixture was added 1.28 g (7.2mmol) of N-bromosuccinimide and then the mixture was warmed to refluxfor 3 hours. A white solid precipitate was removed by filtration, andthe resulting solution was washed with cold 15% NaOH solution (w/v) andcold water. The organic fraction was diluted with 100 ml of CCl₄ and wasdried over NaSO₄, filtered and concentrated in vacuo to yield a yellowoil. Purification by flash chromatography (silica gel, 2% ethyl acetatein hexane) yielded methyl 3-(2-methylbromo)thiophenecarboxylate as ayellow oil. 1.76 g (7.5 mmol) of this crude thiophenecarboxylate wasdissolved in 20 ml of CCl₄ and 2.0 ml (24.7 mmol) of pyridine was added.The solution was heated to 85° C. for 1 hour and then concentrated invacuo to yield a solid residue. The residue was dissolved in 20 ml ofmethanol and added to a solution of 4-nitrosodimethylaniline in 30 ml ofmethanol chilled to 0° C. The solution was allowed to stir a fewminutes. 11.3 ml (11.3 mmol) of 1N NaOH solution was added to the darkgreen solution, and the solution was stirred at 0° C. for 1 hour. Anorange precipitate formed. The suspension was stored at -10° C.overnight to induce further precipitation. The orange solid wascollected by filtration, washed with 200 ml of water and dried in vacuoto yield the title compound as an orange solid.

PMR (CDCl₃): d 3.05 (6H, s), 3.93 (3H, s), 6.71 (2H, d, J=9.2 Hz), 7.37(1H, d, 5.4 Hz), 7.64 (1H, d, 5.4 Hz), 7.80 (2H, d, J=9.2 Hz), 9.70 (1H,s).

3-Carbomethoxy-2-thiophenecarboxaldehyde (Compound 41)

To a 1:1 mixture of 1N H₂ SO₄ and ethyl ether cooled to 0° C. was added0.94 g (3.09 mmol) of methyl 3-2-(imino-(N-oxide)-4-N,N-dimethylaniline)!thiophenecarboxylate inseveral portions over a 15 minute period. The suspension was allowed tostir at 0° C. for 1 hour. A clear, biphasic mixture formed. The layerswere separated and the aqueous phase was washed once with 100 ml ofethyl ether. The organic fractions were combined, washed once with 75 mlof brine, dried over Na₂ SO₄, filtered and concentrated in vacuo toyield the title compound as an orange solid which was used withoutfurther purification.

PMR (CDCl₃): d 3.96 (3H, s), 7.59 (1H, d, 4.9 Hz), 7.64 (1H, dd, J=4.9 ,1.1 Hz), 10.63 (1H, d, J=1.1 Hz).

3-Carbomethoxy-2-furaldehyde (Compound 42)

This compound was prepared substantially in accordance with theliterature procedure of M. Valenta, Collect. Czech. Chem. Commun. 1969,(6)1814-18.

2-Carbomethoxybenzaldehyde (Compound 43)

4.5 g (30 mmol) of 2-carboxybenzaldehyde, 17.1 g (120 mmol) ofiodomethane and 12.4 g (90 mmol) of potassium carbonate were stirred in85 ml of acetone for 24 hours. The solvent was removed by evaporationand the residue was partioned between 50 ml of water and 50 ml of ether.The aqueous layer was washed with 3×50 ml portions of ether. Thecombined organic extracts were washed with 30 ml each of 1M sodiumthiosufate and saturated sodium cloride solutions and dried over MgSO₄.The solvent was removed by evaporation. The residue was subjected toflash chromatography (silica gel, 10% ethyl acetate/hexanes) to give thetitle compound as a clear colorles oil.

PMR (CDCl₃): d 3.98 (3H, s), 7.65-7.68 (2H, m), 7.94-8.00 (2H, m), 10.63(1H, s).

2-Carboethoxybenzaldehyde. (Compound 44)

Using the same procedure as for the preparation of2-carbomethoxybenzaldehyde (Compound 43), but instead using 5.0 g (33mmol) of 2-carboxybenzaldehyde, 23.4 g (150 mmol) of iodoethane and 13.8g (100 mmol) of K₂ CO₃ gave the title compound as a clear colorless oil.

PMR (CDCl₃): d 1.42 (3H, t, J=7.1 Hz), 4.45 (2H, q, J=7.1 Hz), 7.64-7.67(2H, m), 7.92-8.00 (2H, m).

3-(1,3-dioxolane-2-yl)-thiophene

A solution of 28.04 g (250 mmol) of 3-thiophenecarboxaldehyde, 20.2 g(330 mmole) of ethyleneglycol, 10 mg (0.05 mmole) of p-toluenesulfonicacid monohydrate and 25 ml of benzene was heated to reflux untill thecalculated amount of water was removed via a Dean-Stark trap (5 hours).The reaction mixture was allowed to cool to room temperature and waswashed with 30 ml of saturated NaHCO₃ solution. The organic layer wasdried over MgSO₄ and the solvent was removed by evaporation to give thetitle compound as a clear colorles oil.

PMR (CDCl₃): d 3.98-4.15 (4H, m), 5.98 (1H, s), 7.16 (1H, dd, J=5.0, 1.2Hz), 7.32 (1H, dd, J=5.0, 3.0 Hz), 7.42 (1H, dd, J=3.0, 1.2).

2-Carboethoxy-3-thiophenecarboxaldehyde (45)

To a solution of 5.0 g (32 mmole) of 3-(1,3-dioxolane-2)-thiophene in 20ml of ethyl ether was added 22 ml (35 mmole) of n-butyl lithium (1.6M inhexanes). The reaction was warmed to reflux for 15 minutes. The solutionwas then cooled to 0° C. and transfered via canulla into a chilled (0°C.) solution of 3.9 g (35 mmole) of ethyl chloroformate in 20 ml ofethyl ether. This solution was allowed to warm to room temperature andwas added to 20 ml of saturated sodium chloride solution. The organiclayer was separated, the solvent was removed by evaporation and theresidue was dissolved in 20 ml of tetrahydrofuran. 10 ml of 10% HClsolution was added and the solution and was stirred at reflux for 24hours. The majority of the solvent was removed by evaporation and theresidue was partitoned between 30 ml of ethyl ether and 30 ml ofsaturated NaHCO₃ solution. The ether layer was washed with saturatedNaCl solution, dried over MgSO₄ and the solvent was removed byevaporation to yield the title compound as a clear yellow oil.

PMR (CDCl₃); d 1.43 (3H, t, J=6.1 Hz), 4.43 (2H, q, J=6.1 Hz), 7.46 (1H,d, J=5.0 Hz), 7.59 (1H, d, J=5.0 Hz), 10.66 (1H, s).

Methyl 2-4-methyl-4-(3,5,5,8,8-pentamethyl-5,6,7,8-tetrahydronaphthalene)-2-yl-1E,3E-butadien-1-yl!-furan-3-carboxylate(Compound 1)

A suspension of 1.5 g (2.51 mmol) of(5,6,7,8-tetrahydro-3,5,5,8,8-pentamethylnaphthalene-2-yl)but-3-ene-1-yl!triphenylphosphonium bromide (Compound 32), 387 mg (2.51 mmol) of3-carbomethoxy-2-furaldehyde (Compound 42) and 7 ml of 1,2-epoxybutanewere combined under argon and warmed to reflux for 24 hours. Theresulting solution was concentrated in vacuo and the residue purifiedusing flash chromatography (silica gel, 10% ethtyl acetate in hexanes)to give a mixture of geometric isomers. To increase the yield of transisomer about the disubstituted double bond, a solution of the isomericmixture in 30 ml toluene and 40 ml ether was treated with 30 mg (0.01mmol) of iodine and stirred under argon for 24 hours. The solvent wasremoved by evaporation and the residue was purified by flashchromatography (silica gel, 10% ethyl acetate in hexanes). Isomers wereseparated by reverse phase HPLC (Partisil ODS-2; 11% H₂ O inacetonitrile) to give the title compound as a clear pale yellow oil.

PMR (CDCl₃); d 1.26 (12H, S), 1.67 (4H, s), 2.20 (3H, d, J=1.0 Hz), 2.26(3H, s), 3.84 (3H, s), 6.20 (1H, dd, J=11.5, 1.0 Hz), 6.72, 1H, d, J=1.9Hz), 7.06 (1H, s), 7.07 (1H, d, J=15.6 Hz), 7.10 (1H, s), 7.30 (1H, d,J=1.9 Hz), 7.35 (1H, dd, J=11.5, 15.6 Hz).

Methyl 2-4-methyl-4-(3,5,5,8,8-pentamethyl-5,6,7,8-tetrahydronaphthalene)-2-yl-1E,3Z-butadien-1-yl!-furan-3-carboxylate(Compound 2)

Using the same procedures as for the preparation of methyl 2-4-methyl-4-(3,5,5,8,8-pentamethyl-5,6,7,8-tetrahydronaphthalene)-2-yl-1E,3E-butadien-1-yl!-furan-3-carboxylate(Compound 1), the title compound was obtained as a clear pale yellowoil.

PMR (CDCl₃); d 1.25 (6H, s), 1.30 (6H, s), 1.69 (4H, s), 2.12 (3H, s),2.16 (3H, s), 3.83 (3H, s), 6.34 (1H, d, J=11 Hz), 6.64 (1H, d, J=2 Hz),6.65 (1H, dd, J=11, 16 Hz), 6.97 (1H, s), 7.00 (1H, d, J=16 Hz), 7.11(1H, s), 7.16 (1H, d, 2 Hz).

Ethyl 2-4-methyl-4-(3,5,5,8,8-pentamethyl-5,6,7,8-tetrahydronaphthalene)-2-yl-1E,3E-butadien-1-yl!benzoate(Compound 3)

Using the same procedures as for the preparation of methyl 2-4-methyl-4-(3,5,5,8,8-pentamethyl-5,6,7,8-tetrahydronaphthalene)-2-yl-1E,3E-butadien-1-yl!-furan-3-carboxylate(Compound 1) but instead using 7.50 g (12.5 mmol) of(5,6,7,8-tetrahydro-3,5,5,8,8-pentamethylnaphthalene-2-yl)but-3-ene-1-yl!triphenylphosphonium bromide (Compound 32) and 2.47 g of 2-carboethoxybenzaldehyde (Compound 44) suspended in 30 ml of 1,2-epoxybutane, gavethe title compound as a clear pale yellow oil.

PMR (CDCl₃); d 1.28 (6H,s), 1.29 (6H, s), 1.39(3H, t, J=7.1 Hz), 1.68(4H, s), 2.17 (3H, s), 2.27 (3H, s), 4.35 (2H, q, J=7.1 Hz), 6.21 (1H,d, J=11.1 Hz), 7.05 (1H, s), 7.07 (1H, dd, J=11.1, 15.4 Hz), 7.09(1H,s), 7.29 (1H,dd, J=1.6, 7.8 Hz), 7.34 (1H, d, J=15.4 Hz), 7.45-7.50(1H, m), 7.70 (1H, d, ,J=7.3 Hz), 7.86 (1H, dd, J=1.6, 7.8 Hz).

Ethyl 2-4-methyl-4-(3,5,5,8,8-pentamethyl-5,6,7,8-tetrahydronaphthalene)-2-yl-1E,3Z-butadien-1-yl!benzoate(Compound 4).

Using the procedure as for the preparation of ethyl 2-4-methyl-4-(3,5,5,8,8-pentamethyl-5,6,7,8-tetrahydronaphthalene)-2-yl-1E,3E-butadien-1-yl!benzoate(Compound 3), the title compound was isolated as a colorless oil.

PMR (CDCl₃): d 1.26 (6H, s), 1.29 (6H,s), 1.37 (3H, t, J=7.1 Hz), 1.69(4H, s), 2.08 (3H, s), 2.16 (3H,s), 4.33 (2H, q, J=7.1 Hz), 6.32-6.45(2H,m), 6.99 (1H, s), 7.10 (1H, s), 7.15-7.22 (1H, m), 7.31-7.35 (3H,m), 7.80 (1H, d, J=7.2 Hz).

Methyl 2-4-methyl-4-(5,5,8,8-tetramethyl-5,6,7,8-tetrahydronaphthalene)-2-yl-1E,3Z-butadien-1-yl!benzoate(Compound 5)

Using the same procedures as for the preparation of methyl 2-4-methyl-4-(3,5,5,8,8-pentamethyl-5,6,7,8-tetrahydronaphthalene)-2-yl-1E,3E-butadien-1-yl!-furan-3-carboxylate(Compound 1), but instead using 1.5 g (2.57 mmol) of(5,6,7,8-tetrahydro-5,5,8,8-tetramethylnaphthalene-2-yl)but-3-ene-1-yl!triphenylphosphonium bromide (Compound 35) and 422 mg (2.57 mmole) of2-carbomethoxy benzaldehyde (Compound 43) gave the title compound as aclear pale yellow oil.

PMR (CDCl₃); d 1.31 (12H, s), 1.69 (4H, s), 2.18 (3H, s), 3.89 (3H, s),6.36 (1H, d, J=11.1 Hz), 6.96 (1H, dd, 15.6, 11.1 Hz), 7.07 (1H, dd,J=8.1 , 1.9 Hz), 7.15-7.21 (1H, m), 7.26 (1H, d, J=1.7 Hz), 7.29 (1H, d,J=8.1 Hz), 7.28-7.33 (1H, m), 7.38 (1H, d, J=15.6 Hz), 7.49 (1H, d,J=8.1 Hz), 7.81 (1H, dd, J=7.8, 1.4 Hz).

Methyl 2-4-methyl-4-(5,5,8,8-tetramethyl-5,6,7,8-tetrahydronaphthalene)-2-yl-1E,3E-butadien-1-yl!benzoate(Compound 6)

Using the same procedures as for the preparation of methyl 2-4-methyl-4-(5,5,8,8-tetramethyl-5,6,7,8-tetrahydronaphthalene)-2-yl-1E,3Z-butadien-1-yl!benzoate(Compound 5) gave the title compound as a clear pale yellow oil.

PMR (CDCl₃); d 1.28 (6H, s), 1.32 (6H, s), 1.68 (4H, s), 2.25 (3H, s),3.87 (3H, s), 6.71 (1H, d, J=10.2), 7.24 (1H, dd, J=15.2, 10.2 Hz),7.22-7.28 (3H, m), 7.41-7.45 (2H, m), 7.52 (1H, d, J=15.2 Hz), 7.69 (1H,d, J=7.5 Hz), 7.86 (1H, dd, J=7.5, 1.4 Hz).

2-4-Methyl-4-(3,5,5,8,8-pentamethyl-5,6,7,8-tetrahydronaphthalene)-2-yl-1E,3E-butadien-1-yl!benzoicacid (Compound 7)

610 mg (1.52 mmol) of ethyl 2-4-methyl-4-(3,5,5,8,8-pentamethyl-5,6,7,8-tetrahydronaphthalene)-2-yl-1E,3E-butadien-1-yl!benzoate(Compound 3) was suspended in 5ml of tetrahydrofuran and 6.1 ml of 0.5MLiOH solution (3.0 mmol). The suspension was warmed to reflux for 18hours. The solution was evaporated to dryness. The residue was dissolvedin 250 ml H₂ O and washed with 100 ml of ethyl ether. To the aqueouslayer was added 100 ml of ethyl ether and brought to pH=1 with 12M HCl.The aqueous layer was washed with more ethyl ether (3×100 ml). Theorganic fractions were combined, washed with brine, dried over MgSO₄,and evaporated to give the title compound as a white solid.

PMR (d₆ -DMSO); d 1.23 (12H, s), 1.62 (4H, s), 2.15 (3H, s), 2.20 (3H,s), 6.08 (1H, d, J=10.4 Hz), 7.03 (1H, s), 7.11 (1H, s), 7.18 (1H, dd,J=16.6, 10.4 Hz), 7.31 (1H, d, J=16.6 Hz), 7.32-7.36 (1H, m), 7.51-7.57(1H, m), 7.77 (1H, dd, J=7.8, 1.2 Hz), 7.88 (1H, d, J=7.8 Hz).

2-4-Methyl-4-(3,5,5,8,8-pentamethyl-5,6,7,8-tetrahydronaphthalene)-2-yl-1E,3Z-butadien-1-yl!benzoicacid (Compound 8)

Using the same procedure as for the preparation of 2-4-methyl-4-(3,5,5,8,8-pentamethyl-5,6,7,8-tetrahydronaphthalene)-2-yl-1E,3E-butadien-1-yl!benzoicacid (Compound 7) but instead using 0.5 g (1.2 mmol) of ethyl 2-4-methyl-4-(3,5,5,8,8-pentamethyl-5,6,7,8-tetrahydronaphthalene)-2-yl-1E,3Z-butadien-1-yl!benzoate(Compound 5), 5 ml of tetrahydrofuran, and 5 ml 0.5M LiOH (2.5 mmol),gave the title compound as a white solid.

PMR (CDCl₃); d 1.27 (6H, s), 1.30 (6H, s), 1.69 (4H, s), 2.12 (3H, s),2.19 (3H, s), 6.38-6.49 (2H, m), 7.00 (1H, s), 7.11 (1H, s), 7.20-7.25(1H, m), 7.38-7.43 (3H, m), 7.97 (1H, d, J=1.2 Hz).

2-4-Methyl-4-(3,5,5,8,8-pentamethyl-5,6,7,8-tetrahydronaphthalene)-2-yl-1E,3Z-butadien-1-yl!-furan-3-carboxylicacid (Compound 9)

Using the same procedures as for the preparation of 2-4-methyl-4-(3,5,5,8,8-pentamethyl-5,6,7,8-tetrahydronaphthalene)-2-yl-1E,3E-butadien-1-yl!benzoicacid (Compound 7), but instead using 266 mg (0.69 mmol) of methyl 2-4-methyl-4-(3,5,5,8,8-pentamethyl-5,6,7,8-tetrahydronaphthalene)-2-yl-1E,3Z-butadien-1-yl!-furan-3-carboxylate(Compound 2), 5.5 ml of tetrahydrofuran and 2.75 ml of 0.5M LiOH (1.37mmol), gave the title compound as a white solid.

PMR (CDCl₃); d 1.26 (6H, s), 1.31 (6H, s), 1.70 (4H, s), 2.14 (3H, s),2.17 (3H, s), 6.36 (1H, d, J=11.3 Hz), 6.70 (1H, dd, J=15.6, 11.3 Hz),6.72 (1H, d, J=2.0 Hz), 6.98 (1H, s), 7.04 (1H, d, J=15.6 Hz), 7.13 (1H,s), 7.19 (1H, d, J=2.0 Hz).

2-4-Methyl-4-(3,5,5,8,8-pentamethyl-5,6,7,8-tetrahydronaphthalen)-2-yl-1E,3E-butadien-1-yl!furan 3-carboxylic acid (Compound 10

Using the same procedures as for the preparation of 2-4-methyl-4-(3,5,5,8,8-pentamethyl-5,6,7,8-tetrahydronaphthalene)-2-yl-1E,3E-butadien-1-yl!benzoicacid (Compound 7), but instead using 480 mg (1.27 mmol) of compoundmethyl 2-4-methyl-4-(3,5,5,8,8-pentamethyl-5,6,7,8-tetrahydronaphthalene)-2-yl-1E,3E-butadien-1-yl!-furan-3-carboxylate(Compound 1), 10 ml of tetrahydrofuran and 5.0 ml of 0.5M LiOH (2.50mmol), gave the title compound as a white solid.

PMR (CDCl₃); d 1.28 (6H, s),1.29 (6H, s), 1.68 (4H, s), 2.21 (3H, s),2.25 (3H, s), 6.20(1H, d, J=12.0 Hz), 6.77 (1H, d, J=1.9 Hz), 7.05 (1H,s), 7.08 (1H, d, J=15.0 Hz), 7.09 (1H, s), 7.33 (1H, d, J=1.9 Hz), 7.38(1H, dd, J=15.0, 12.0 Hz).

Methyl 2-4-methyl-4-(5,5,8,8-tetramethyl-5,6,7,8-tetrahydronaphthalen)-2-yl-1E,3E-butadien-1-yl!furan 3-carboxylate (Compound 11)

Using the same procedure as for the preparation of methyl 2-4-methyl-4-(3,5,5,8,8-pentamethyl-5,6,7,8-tetrahydronaphthalene)-2-yl-1E,3E-butadien-1-yl!-furan-3-carboxylate(Compound 1), but instead using 2.53 g (4.34 mmol) of(5,6,7,8-tetrahydro-5,5,8,8-tetramethylnaphthalene-2-yl )but-3-ene-1-yl! triphenylphosphonium bromide (Compound 35) and 0.67 g(4.34 mmol) of 3-carbomethoxy-2-furaldehyde (Compound 42) suspended in30 ml of 1,2-epoxybutane, gave the title compound as a clear colorlessoil.

PMR (CDCl₃); d 1.29 (6H, s), 1.33 (6H, s), 1.70 (4H, s), 2.28 (3H, s),3.86 (3H, s), 6.68 (1H, d, J=11.5 Hz), 6.72 (1H, d, J=2.0 Hz), 7.15 (1H,d, J=15.5 Hz), 7.25-7.31 (3H, m), 7.40 (1H, dd, J=11.5, 15.5 Hz), 7.45(1H, s).

Methyl 2-4-methyl-4-(5,5,8,8-tetramethyl-5,6,7,8-tetrahydronaphthalen)-2-yl-1E,3Z-butadien-1-yl! furan 3-carboxylate (Compound 12)

Using the same procedure as for the preparation of methyl 2-4-methyl-4-(5,5,8,8-tetramethyl-5,6,7,8-tetrahydronaphthalen)-2-yl-1E,3E-butadien-1-yl! furan 3-carboxylate (Compound 11) gave the titlecompound as a clear colorless oil.

PMR (CDCl₃); d 1.30 (6H, s), 1.31 (6H, s), 1.71 (4H, s), 2.21 (3H, s),3.84 (3H, s), 6.33 (1H, d, J=11.5 Hz), 6.66 (1H, d, J=2.0 Hz), 7.03 (1H,d, J=15.8 Hz), 7.07 (1H, dd, J=2.0, 8.6 Hz), 7.15 (1H, dd, J=11.5, 15.8Hz), 7.16 (1H, d, J=2.0 Hz), 7.23 (1H, d, J=2.0 Hz), 7.30 (1H, d, J=8.6Hz).

2-4-Methyl-4-(5,5,8,8-tetramethyl-5,6,7,8-tetrahydronaphthalen)-2-yl-1E,3E-butadien-1-yl! furan 3-carboxylic acid (Compound 13)

710 mg (1.9 mmol) of methyl 2-4-methyl-4-(5,5,8,8-tetramethyl-5,6,7,8-tetrahydronaphthalen)-2-yl-1E,3E-butadien-1-yl! furan 3-carboxylate (Compound 11) was suspended in 20ml of tetrahydrofuran and 2.0 ml of 2N KOH solution (3.0 mmol). Thesuspension was stirred at room temperature for 24 hours. The solutionwas evaporated to dryness. The residue was dissolved in 250 ml H₂ O andwashed with 100 ml of ethyl ether. To the aqueous fraction was added 100ml of ethyl ether and brought to pH=1 with 12M HCl. The aqueous layerwas washed with ethyl ether (3×100 ml). The organic fractions werecombined, washed with brine, dried over MgSO₄, and evaporated to givethe title compound as a white solid.

PMR (CDCl₃); d 1.30 (6H, s), 1.34 (6H, s), 1.71 (4H, s), 2.26 (3H, s),6.71 (1H, d, J=11 Hz), 6.78 (1H, d, J=2 Hz), 7.16 (1H, d, J=15.5 Hz),7.25-7.31 (3H, m), 7.45 (1H, dd, J=11, 15.5 Hz), 7.46(1H, s).

2-4-Methyl-4-(5,5,8,8-tetramethyl-5,6,7,8-tetrahydronaphthalen)-2-yl-1E,3Z-butadien-1-yl!furan 3-carboxylic acid (Compound 14)

Using the same procedure as for the preparation of 2-4-methyl-4-(5,5,8,8-tetramethyl-5,6,7,8-tetrahydronaphthalen)-2-yl-1E,3E-butadien-1-yl!furan 3-carboxylic acid (Compound 13), but instead using 120 mg (0.32mmol) of methyl 2-4-methyl-4-(5,5,8,8-tetramethyl-5,6,7,8-tetrahydronaphthalen)-2-yl-1E,3Z-butadien-1-yl!furan 3-carboxylate (Compound 12) gave the title compound as a whitesolid.

PMR (CDCl₃); d 1.31 (6H, s) , 1.32 (6H, s), 1.72 (4H, s), 2.23 (3H, s),6.36 (1H, d, J=11.5 Hz), 6.71 (1H, d, J=2.0 Hz), 7.07 (1H, d, J=15.8Hz), 7.08 (1H, dd, J=2.0, 8.6 Hz), 7.18-7.24 (3H, m), 7.30 (1H, d, J=8.5Hz).

Ethyl 3-4-methyl-4-(3,5,5,8,8-pentamethyl-5,6,7,8-tetrahydronaphthalen)-2-yl-1E,3E-butadien-1-yl!thiophene2-carboxylate (Compound 15)

Using the same procedures as for the preparation of methyl 2-4-methyl-4-(3,5,5,8,8-pentamethyl-5,6,7,8-tetrahydronaphthalene)-2-yl-1E,3E-butadien-1-yl!-furan-3-carboxylate(Compound 1), but instead using 3.56 g (5.98 mmol) of(5,6,7,8-tetrahydro-3,5,5,8,8-pentamethylnaphthalene-2-yl)but-3-ene-1-yl!triphenylphosphoniumbromide (Compound 32) and 1.1 g (5.98 mmol) of2-carboethoxy-3-thiophenecarboxaldehyde (Compound 45) suspended in 20 mlof 1,2-epoxybutane, gave the title compound as a clear pale yellow oil.

PMR (CDCl₃); d 1.28 (6H, s), 1.29 (6H, s), 1.37 (3H, t, J=7.1 Hz), 1.68(4H, s), 2.17 (3H, s), 2.26 (3H, s),4.33 (2H, q, J=7.1 Hz), 6.21 (1H, d,J=11.5 Hz), 7.06 (1H, s), 7.09 (1H, s), 7.14 (1H, dd, J=11.5, 15.5 Hz),7.40 (1H, d, J=5.3 Hz), 7.42 (1H, d, J=5.3 Hz), 7.52 (1H, d, J=15.5 Hz).

Ethyl 3-4-methyl-4-(3,5,5,8,8-pentamethyl-5,6,7,8-tetrahydronaphthalen)-2-yl-1E,3Z-butadien-1-yl!thiophene 2-carboxylate (Compound 16)

Using the same procedures as for the preparation of ethyl 3-4-methyl-4-(3,5,5,8,8-pentamethyl-5,6,7,8-tetrahydronaphthalen)-2-yl-1E,3E-butadien-1-yl!thiophene 2-carboxylate (Compound 15), gave the title compound as aclear yellow oil.

PMR (CDCl₃); d 1.25 (6H, s), 1.31 (6H, s), 1.38 (3H, t, J=7.1 Hz), 1.69(4H, s), 2.11 (3H, s), 2.16 (3H, s),4.34 (2H, q, J=7.1 Hz), 6.35 (1H, d,J=10.9 Hz), 6.45 (1H, dd, J=10.9, 15.3 Hz), 6.97 (1H, s), 7.01 (1H, d,J=5.3 Hz), 7.11 (1H, s), 7.26 (1H, d, J=5.3 Hz), 7.52 (1H, d, J=15.3Hz).

3-4-Methyl-4-(3,5,5,8,8-pentamethyl-5,6,7,8-tetrahydronaphthalen)-2-yl-1E,3E-butadien-1-yl!thiophene 2-carboxylic acid (Compound 17)

Using the same procedure as for the preparation of 2-4-methyl-4-(3,5,5,8,8-pentamethyl-5,6,7,8-tetrahydronaphthalene)-2-yl-1E,3E-butadien-1-yl!benzoicacid (Compound 7), but instead using 525 mg (1.2 mmol) of ethyl 3-4-methyl-4-(3,5,5,8,8-pentamethyl-5,6,7,8-tetrahydronaphthalen)-2-yl-1E,3E-butadien-1-yl!thiophene 2-carboxylate (Compound 15), 5 ml of tetrahydrofuran, and 5 ml0.5M LiOH (2.5 mmol), gave the title compound as a white solid.

PMR (CDCl₃); d 1.23 (6H, s), 1.24 (6H, s), 1.62 (4H, s), 2.16 (3H, s),2.20 (3H, s), 6.07 (1H, d, J=9.5 Hz), 7.03 (1H, s), 7.12 (1H, s), 7.33(1H, dd, J=9.5, 15.5 Hz), 7.43 (1H, d, J=15.5 Hz), 7.74 (1H, d, J=5.4Hz), 7.77 (1H, d, J=5.4 Hz).

3-4-Methyl-4-(3,5,5,8,8-pentamethyl-5,6,7,8-tetrahydronaphthalen)-2-yl-1E,3Z-butadien-1-yl!thiophene 2-carboxylic acid (Compound 18)

Using the same procedure as for the preparation of 2-4-methyl-4-(3,5,5,8,8-pentamethyl-5,6,7,8-tetrahydronaphthalene)-2-yl-1E,3E-butadien-1-yl!benzoicacid (Compound 7) but instead using 113 mg (0.27 mmol) of ethyl 3-4-methyl-4-(3,5,5,8,8-pentamethyl-5,6,7,8-tetrahydronaphthalen)-2-yl-1E,3Z-butadien-1-yl!thiophene 2-carboxylate (Compound 16), 5 ml of tetrahydrofuran, and 5 ml0.5M LiOH (2.5 mmol), gave the title compound as a white solid.

PMR (CDCl₃); d 1.26 (6H, s), 1.32 (6H, s),1.70 (4H, s), 2.13 (3H, s),2.17 (3H, s), 6.38 (1H, d, J=11 Hz), 6.50 (1H, dd, J=11, 15.3 Hz), 7.00(1H, s), 7.05 (1H, d, J=5.3 Hz), 7.12 (1H, s), 7.37 (1H, d, J=5.3 Hz),7.45 (1H, d, J=15.3 Hz).

Ethyl 3-4-methyl-4-(3,5,5,8,8-pentamethyl-5,6,7,8-tetrahydronaphthalene)-2-yl-1Z,3E-butadiene-1yl!-2-furanoate(Compound 19)

A suspension of 3.68 g (6.2 mmol) of(5,6,7,8-tetrahydro-3,5,5,8,8-pentamethylnaphthalene-2-yl)but-3-ene-1-yl!triphenylphosphonium bromide (Compound 32), 0.69 g (4.1 mmol) of2-carboethoxy-3-furaldehyde (Compound 40) and 35 ml of 1,2-epoxybutanewere combined under argon and warmed to reflux for 14.5 hours. Theresulting solution was concentrated in vacuo and the residue purified byflash chromatography (silica gel, 3% ethyl acetate in hexane) to givethe title compound as an off-white solid. Further amounts of thecompound were isolated from impure chromatography fractions by normalphase HPLC (Parisil 10, 1% ethyl acetate in hexane).

PMR (CDCl₃): d 1.26 (6H, s), 1.29 (6H, s), 1.41 (3H, t, J=7.1 Hz), 1.67(4H, s), 2.15 (3H, s), 2.25 (3H, s), 4.39 (2H, q, J=7.1 Hz), 6.46 (1H,d, J=11.7 Hz), 6.69 (1H, dd, J=11.7, 11.3 Hz), 6.72 (1H, d, J=1.8 Hz),6.88 (1H, d, J=11.3 Hz), 7.03 (1H, s), 7.09 (1H, s), 7.44 (1H, d, J=1.8Hz).

Methyl 2-4-methyl-4-(3,5,5,8,8-pentamethyl-5,6,7,8-tetrahydronaphthalene)-2-yl-1Z,3E-butadiene-1-yl!-3-thiophenecarboxylate(Compound 20)

Using the same procedure as for the preparation of ethyl 3-4-methyl-4-(3,5,5,8,8-pentamethyl-5,6,7,8-tetrahydronaphthalene)-2-yl-1Z,3E-butadiene-1-yl!-2-furanoate(Compound 19), but instead using 2.42 g (4.05 mmol) of(5,6,7,8-tetrahydro-3,5,5,8,8-pentamethylnaphthalene-2-yl)but-3-ene-1-yl!triphenylphosphonium bromide (Compound 32) and 0.46 g (2.7 mmol) of3-carbomethoxy-2-thiophenecarboxaldehyde (Compound 41) suspended in 30ml of 1,2-epoxybutane refluxed for 19 hours yielded a mixture ofisomers. Purification by flash chromatography (silica, 2% ethyl acetatein hexane) yielded a mixture of geometric isomers. Isomers were purifiedby normal phase HPLC (Partisil 10 PAC, 1% ethyl acetate in hexane) togive the title compound as a yellow foamy solid.

PMR (CDCl₃): d 1.27 (6H, s), 1.29 (6H, s), 1.67 (4H, s), 2.18 (3H, s),2.28 (3H, s), 3.86 (3H, s), 6.76 (1H, d, J=12.0 Hz), 6.69 (1H, dd,J=12.0, 10.3 Hz), 7.09 (2H, s), 7.14 (1H, d, J=5.4 Hz), 7.39 (1H, d,J=10.3 Hz), 7.43 (1H, d, J=5.4 Hz).

Methyl 2-4-methyl-4-(3,5,5,8,8-pentamethyl-5,6,7,8-tetrahydronaphthalene)-2-yl-1E,3E-butadiene-1-yl!-3-thiophenecarboxylate(Compound 21)

Using the same procedure as for the preparation of methyl 2-4-methyl-4-(3,5,5,8,8-pentamethyl-5,6,7,8-tetrahydronaphthalene)-2-yl-1Z,3E-butadiene-1-yl!-3-thiophenecarboxylate(Compound 20) the title compound was obtained as a yellow foamy solid.

PMR (CDCl₃): d 1.28 (6H, s), 1.29 (6H, s), 1.68 (4H, s), 2.18 (3H, s),2.26 (3H, s), 3.85 (3H, s), 6.20 (1H, d, J=11.6 Hz), 7.04 (1H, d, J=4.8Hz), 7.05 (1H, s), 7.09 (1H, s), 7.12 (1H, dd, J=11.6, 15.5 Hz), 7.39(1H, d, J=5.4 Hz), 7.60 (1H, d, J=15.5 Hz).

2-4-methyl-4-(3,5,5,8,8-pentamethyl-5,6,7,8-tetrahydronaphthalene)-2-yl-1E,3E-butadiene-1-yl!-3-thiophenecarboxylicacid (Compound 22)

To a solution of 0.73 g (1.79 mmol) of methyl 2-4-methyl-4-(3,5,5,8,8-pentamethyl-5,6,7,8-tetrahydronaphthalene)-2-yl-1E,3E-butadiene-1-yl!-3-thiophenecarboxylate(Compound 21) in 36 ml of tetrahydrofuran was added 9 ml (9 mmol) of1.0M LiOH solution. The solution was allowed to stir in the dark at roomtemperature for 1 week. The solution was concentrated in vacuo, dilutedwith water and stirred with a small amount of hexane. The layers wereseparated. The aqueous phases was partitioned with 200 ml of ethylether, acidified to pH<1 with 1N H₂ SO₄ solution and diluted with brine.The organic phase was dried over Na₂ SO₄ and concentrated in vacuo to ayellow foam. Purification by flash chromatography (silica gel, 10% ethylacetate in hexane) followed by recrystallization from boilingacetonitrile yielded the title compound as a yellow crystalline solid.

PMR (d₆ DMSO-): d 1.27 (6H, s) , 1.28 (6H, s), 1.68 (4H, s), 2.19 (3H,s), 2.26 (3H, s), 6.20 (1H, d, J=11.4 Hz), 7.04 (1H, s), 7.07 (1H, d,J=5.5 Hz), 7.08 (1H, s), 7.16 (1H, dd, J=11.4, 15.4 Hz), 7.45 (1H, d,J=5.3 Hz), 7.61 (1H, d, J=15.4 Hz).

2-4-Methyl-4-(3,5,5,8,8-pentamethyl-5,6,7,8-tetrahydronaphthalene)-2-yl-1Z,3E-butadiene-1-yl!-3-thiophenecarboxylicacid (Compound 23)

Using the same procedure as for the preparation of 2-4-methyl-4-(3,5,5,8,8-pentamethyl-5,6,7,8-tetrahydronaphthalene)-2-yl-1E,3E-butadiene-1-yl!-3-thiophenecarboxylicacid (Compound 22), but instead using 0.37 g (0.90 mmol) of methyl 2-4-methyl-4-(3,5,5,8,8-pentamethyl-5,6,7,8-tetrahydronaphthalene)-2-yl-1Z,3E-butadiene-1-yl!-3-thiophenecarboxylate(Compound 20) 4.5 ml (4.5 mmol) of 1.0M LiOH solution and 18 ml of THFafter work up (pH=2) gave the title compound as a yellow solid.

PMR (d₆ DMSO-): d 1.23 (6H, s), 1.24 (6H, s), 1.62 (4H, s), 2.14 (3H,s), 2.23 (3H, s), 6.63 (1H, d, J=11.9 Hz ), 6.73 (1H, dd, J=11.5, 11.9Hz), 7.07 (1H, s), 7.14 (1H, s), 7.38 (1H, d, J=5.4 Hz), 7.43 (1H, d,J=11.5 Hz), 7.51 (1H, d, J=5.4 Hz).

Methyl 2-4-methyl-4-(3,5,5,8,8-pentametyl-5,6,7,8-tetrahydronaphthalene)-2-yl-1E,3E-butadien-1-yl!benzoate(Compound 24)

Using the same procedures as for the preparation of methyl 2-4-methyl-4-(3,5,5,8,8-pentamethyl-5,6,7,8-tetrahydronaphthalene)-2-yl-1E,3E-butadien-1-yl!furan-3-carboxylate(Compound 1), but instead using 0,750 g (1.25 mmol) of(5,6,7,8-tetrahydro-3,5,5,8,8-pentamethylnaphthalene-2-yl)but-3-ene-1-yl!triphenylphosphonium bromide (Compound 32) and 0.207 g (1.26 mmol) of2-carbomethoxy benzaldehyde (Compound 43) suspended in 3.5 ml of1,2-epoxybutane, gave the title compound as a clear pale yellow oil.

PMR (CDCl₃); δ 1.28 (12H, s), 1.68 (4H, s), 2.17 (3H, s), 2.27 (3H, s),3.89 (3H, s), 6.23 (1H, d, J=11 Hz), 7.08 (1H, s), 7.07 (1H, dd, J=11.1(16 Hz), 7.10 (1H, s), 7.29 (1H, dd, J=1.6, 7.8 Hz), 7.37 (1H, d, J=16Hz), 7.46-7.51 (1H, m), 7.72 (1H, d, J=7.8 Hz), 7.87 (1H, dd, J=1.6, 7.8Hz).

What is claimed is:
 1. A compound of the formula ##STR6## wherein R₁ -R₄independently are hydrogen, lower alkyl of 1 to 6 carbons, Cl, Br, orI;R₅ is hydrogen, lower alkyl of 1 to 6 carbons, CI, Br, I, lower alkoxyor lower thioalkoxy of 1-6 carbons; R₆ is hydrogen, lower alkyl, Cl, Br,I, OR₁₁, SR₁₁, OCOR₁₁, SCOR₁₁, NH2, NHR₁₁, N(R₁₁)₂, NHCOR₁₁ OR NR₁₁--COR₁₁ ; R₂₀ is independently hydrogen or lower alkyl; A is (CH₂)_(n)where n is 0-5; B is COOH or a pharmaceutically acceptable salt thereof,COOR₈, CONR₉ R₁₀, --CH₂ OH, CH₂ OCOR₁₁, where R₈ is an alkyl group of 1to 10 carbons, or a cycloalkyl group of 5 to 10 carbons, or R₈ is phenylor lower alkylphenyl, R₉ and R₁₀ independently are hydrogen, an alkylgroup of 1to 10 carbons, or a cycloalkyl group of 5-10 carbons, orphenyl or lower alkylphenyl, R₁₁ is lower alkyl, phenyl or loweralkylphenyl.
 2. A compound in accordance with claim 1 wherein the A--Bgroup is (CH₂)_(n) --COOH, (CH₂)_(n) --COOR₈ or (CH₂)_(n) --CONR₉ R₁₀,and n is 0, R₁ through R₄ and R₆ are H or methyl, R₅ is H, and R₂₀ ismethyl.
 3. A compound in accordance with claim 2 which is selected fromthe group consisting of methyl 2-4-methyl-4-(3,5,5,8,8-pentamethyl-5,6,7,8-tetrahydronaphthalene)-2-yl-1E,3E-butadien-1-yl!-benzoate,ethyl 2-4-methyl-4-(3,5,5,8,8-pentamethyl-5,6,7,8-tetrahydronaphthalene)-2-yl-1E,3E-butadien-1-yl!benzoate,ethyl 2-4-methyl-4-(3,5,5,8,8-pentamethyl-5,6,7,8-tetrahydronaphthalene)-2-yl-1E,3Z-butadien-1-yl!benzoate,methyl 2-4-methyl-4-(5,5,8,8-tetramethyl-5,6,7,8-tetrahydro-naphthalene)-2-yl-1E,3Z-butadien-1-yl!benzoate,methyl 2-4-methyl-4-(5,5,8,8-tetramethyl-5,6,7,8-tetrahydronaphthalene)-2-yl-1E,3E-butadien-1-yl!benzoate,2-4-methyl-4-(3,5,5,8,8-pentamethyl-5,6,7,8-tetrahydronaphthalene)-2-yl-1E,3E-butadien-1-yl!benzoicacid and 2-4-methyl-4-(3,5,5,8,8-pentamethyl-5,6,7,8-tetrahydronaphthalene)-2-yl-1E,3Z-butadien-1-yl!benzoicacid.
 4. A method of treating a disease or condition of a mammal whichis susceptible to treatment by a retinoid-like compound, with apharmaceutical composition containing an effective amount of a compoundin accordance with claim 1 said disease or condition being selected fromdermatoses, Darier's disease, psoriasis, icthyosis, eczema, atopicdermatitis, malignant hyperproliferative diseases, artherosclerosis andrestenosis resulting from neointiural hyperproliferation, endometrialhyperplasia, benign prostatic hypertrophy, proliferative vitrealretirropathy and dysplasias, autoimmune diseases, immunologicaldisorders, chronic inflammatory diseases, diseases associated with lipidmetabolism and transport such as dyslipidemias, wound healing, dry eyesyndrome and sun damage to skin.